Elena and I ran insect protein expression of a secreted protein that is heavily post-translationally modified. It was particularly cool to count cells with a little counter device (I felt like a bouncer in the club)… This system is tougher than E.coli, no doubt. We did isolate some good stuff off the Ni bead column. We’ll purify it tomorrow. After that I spent some time with Gena Poda at OICR who taught me docking. I am loving this experience – I get to learn the whole process of probe development, from cloning to expression and modelling.

Later on, thanks to Jeff St. Denis (my PhD student), we had a trip to the Oakland A’s/Blue Jays’ game. Jeff bought the tickets and we all had a blast. Here is a pic (about half of my lab was able to come). Below you see Joy, Jeff, Megan, Shinya, Chris, Sean (top row); Sonia, Ben (bottom row). I hope we do it more often while the weather is still good (maybe a bbq at my place, eventually?)…

I was looking through some old photos and found this one from 1999!

From left to right: Alicja, Agniezhka, Juan, myself, Shahla, Omar, Jim, Tung, and Raju. Alicja, Juan, Omar and Agniezhka were among my first undergraduate students. Shahla, Jim, and Tung were my first graduate students and Raju – my first postdoc. Out of this great group of people I see Raju a lot these days. He works at OICR (Ontario Institute for Cancer Research) and is doing great. We should have a reunion with everyone at some point… Hope everyone else is doing well, although people scattered are all over the place (more on that later).

We all got this really sad news earlier today: Professor Tony Pawson of Mount SInai has died.

http://www.thestar.com/life/health_wellness/2013/08/08/renowned_toronto_genetic_researcher_dr_tony_pawson_dies.html

Tony was one of the titans in the field of cell signalling and, in fact, one of the founders of this field. My own interest in pursuing disrupters of protein-protein interactions was, to a large extent, based on my interactions with Tony. Over the past three years Tony, Shawn Li, Jeff Wrana, and I have shared an ORF grant aimed at finding specific protein domain ligands. We will dearly miss Tony and his insights.

I am certain that my lab and I will take his legacy as an inspiration to go forward and continue pursuing science at the chemistry/biology interface. Ironically, today (as part of my sabbatical work at SGC) we got our second protein crystal (thanks a lot to Elena and Aiping, again!!!) and this is one of the ones Tony was really keen on. Below are the views and the crystal structure that shows (in yellow) the two aromatic cages that recognize lysine-containing fragments. We will remember Tony dearly and will work tirelessly toward some of the common goals we have shared…

Apparently, my PhD student Serge Zaretsky is not great at soccer… He emailed me yesterday from the Colby Sawyer College, where he is attending the Gordon Conference (Medicinal Chemistry). Those industry people (who form the majority of attendees at this GRC) are just too good… However, and more importantly, Serge got one of three poster awards and will present his work as a short talk tomorrow morning in front of the world’s leading medicinal chemists. It seems that there is a lot of interest in macrocycles (Serge’s area of expertise). No pressure there, Serge! Good luck!

The lads (Serge Zaretsky and Adam Zajdlik) are at the Gordon Conference on Medicinal Chemistry this coming week. I am really looking forward to hearing how their research has been received. They both have really cool stories centred around boron-containing heterocycles and their biology (Adam) and peptide macrocycles made with our evolving aziridine aldehyde methods (Serge). It is almost 9pm now and I think I know where they are going to be soon after the talks are done! Below are Serge’s and Adam’s pics and a couple of snip bits about some of the science they are presenting.

Here it is, guys. The structure is 2.4 Angstrom resolution, which is not too bad for a start. This happens to be a PWWP domain that recognizes methylated lysine containing peptides. The goal now is to design ligands on the basis of the small molecule fragment (you can see it) that has co-crystallized. I was talking to my PhD student Rebecca the other day and she is very keen to tackle this problem. Today I learned that another crystal might be sent out to the synchrotron soon. That will be awesome. Big-time thanks to Elena (who teaches me protein crystallography) and to Aiping Dong, who is the crystallography expert. He is amazing. I love chasing proteins!

I flew into Boston last night to give a talk at Novartis. I had a great time there today. Donovan Chin (Senior Investigator at the NIBR) was my host. I had a lot of fun hearing about their interests in molecules that are also dear to our hearts. I am talking about peptide macrocycles. Scott Lokey of the UCSC was also here at Novartis last week. Scott is doing some trailblazing work trying to understand the cell permeability of cyclic peptides.

It is clear that the industry appetite to macrocycles is high, particularly with regard to gauging their complex stereochemical preferences… It is eye-opening to talk to people in industry who do this for a living. When I hear that docking a small molecule takes a couple of minutes (I refer to computational docking into a binding site of a protein target), whereas the same process for a macrocycle is close to 18 hours, I really wonder how anyone will get the “heavy lifting” (to use the language of Dr. Andrew Roughton, the COO of Encycle Therapeutics, a company I founded in 2012) done in this space. It is, nonetheless, a fascinating problem and we are going to deal with it heads-on as a community. Naively, I asked Donovan about why does it really matter to be “right” in a complicated maze of conformations that are differentiated by a fraction of a kcal/mol. However, it is important to keep in mind that this thing is additive… To use Donovan’s analogy, it is like walking in the streets of Paris (or any other city with a complex web of streets): one wrong turn and your mistake is exacerbated such that the “real destination” will never be found… If we have a cycle that is composed of (say) 8 amino acids – once you add all the rotors, it is easy to see that this is a tough problem to crack computationally.

We needed to have some beers at the end of this day and went to this place called “Catalyst” right next to MIT. My former student Tim Rasmusson, who works at Novartis, came out – it was cool to see him! He is doing great. I hoped Ben Rotstein and Zhi He might join us (former PhD students who are now doing their PDFs at Harvard and MIT, respectively), but they were busy. I am at the airport now and will blog about my protein crystals tomorrow. The data is in!